Germline Mutations In BRCA1-associated Protein 1 Research Articles

Roles of the BAP1 Tumor Suppressor in Cell Metabolism.

BRCA1-associated protein 1 (BAP1) is emerging as an intensively studied cancer-associated gene. Germline mutations in BAP1 lead to a cancer syndrome, and somatic loss is found in several cancer types. BAP1 encodes a deubiquitinase enzyme, which plays key roles in cell-cycle regulation, cell death, and differentiation. Recent studies have demonstrated that BAP1 is also involved in several aspects of cellular metabolism, including metabolic homeostasis, glucose utilization, control of ferroptosis, and stress response. A better knowledge of the metabolic roles of cancer-associated genes is important to understanding tumor initiation and progression, as well as highlighting potential therapeutic avenues. With this review, we summarize the current knowledge regarding BAP1-mediated regulation of metabolic activities that may support new strategies to treat BAP1-mutated cancers.

Clinical and dermoscopic features of cutaneous BAP1-inactivated melanocytic tumors: Results of a multicenter case-control study by the International Dermoscopy Society

Multiple BRCA1-associated protein 1 (BAP1)-inactivated melanocytic tumors (BIMTs) have been associated with a familial cancer syndrome involving germline mutations in BAP1. We sought to describe the clinical and dermoscopic features of BIMTs. This was a retrospective, multicenter, case-control study. Participating centers contributed clinical data, dermoscopic images, and histopathologic data of biopsy-proven BIMTs. We compared the dermoscopic features between BIMTs and control patients. The dataset consisted of 48 BIMTs from 31 patients (22 women; median age 37years) and 80 control patients. Eleven patients had a BAP1 germline mutation. Clinically, most BIMTs presented as pink, dome-shaped papules (n=24). Dermoscopically, we identified 5 patterns: structureless pink-to-tan with irregular eccentric dots/globules (n=14, 29.8%); structureless pink-to-tan with peripheral vessels (n=10, 21.3%); structureless pink-to-tan (n=7, 14.9%); a network with raised, structureless, pink-to-tan areas (n=7, 14.9%); and globular pattern (n=4, 8.5%). The structureless with eccentric dots/globules pattern and network with raised structureless areas pattern were only identified in BIMT and were more common in patients with BAP1 germline mutations (P<.0001 and P=.001, respectively). Limitations included our small sample size, retrospective design, the absence of germline genetic testing in all patients, and inclusion bias toward more atypical-looking BIMTs. Dome-shaped papules with pink-to-tan structureless areas and peripheral irregular dots/globules or network should raise the clinical suspicion for BIMT.

Genomic profiling of the genes on chromosome 3p in sporadic clear cell renal cell carcinoma

Somatic mutations of the BRCA1 associated protein-1 (BAP1) gene, which maps to 3p21, have been found in several tumors including malignant mesothelioma, uveal melanoma, and renal cell carcinoma (RCC). The role of BAP1 inactivation in tumor development remains unclear. It has been reported that Vhl knock-out mice did not develop RCC, but Vhl knock-out mice with single allele loss of Bap1 in nephron progenitor cells developed RCC, indicating that Bap1 inactivation may be essential in murine renal tumorigenesis. To clarify the role of BAP1 in human RCC development, we performed mutation analyses, including copy number detection of BAP1 and assessment of allelic imbalance using microsatellite polymorphisms on 3p, in 45 RCC samples derived from 45 patients without VHL or BAP1 germline mutation. Additionally, we analyzed the sequences of the VHL, PBRM1, and SETD2 genes, and examined promoter methylation of VHL. Using immunostaining, we also checked for expression of BAP1 protein, which is normally located in the nuclei. None of the RCCs had biallelic deletion of BAP1, but five (11.1%) showed a biallelic mutation (four with a sequence-level mutation with monoallelic loss and one with a biallelic sequence-level mutation); these cells were negative for nuclear BAP1 staining. These patients had worse recurrence-free survival than the patients without a biallelic mutation (p=0.046). However, there were no significant differences in worse outcome by multivariate analysis combined with age, T stage, histological subtype, infiltration and vascular invasion. In 35 RCCs (77.8%), monoallelic loss of BAP1 was accompanied by VHL biallelic mutation or VHL promoter hypermethylation. In five RCCs (11.1%), we detected 3p loss-of-heterozygosity, but the copy number of BAP1 was normal. Surprisingly, nuclear staining of BAP1 was negative in 10 out of 31 tumors (32.3%) with hemizygous normal BAP1, suggesting that haploinsufficiency may relate to RCC development.

BAP1 and BRAFV600E expression in benign and malignant melanocytic proliferations.

BAP1 (BRCA1-associated protein 1) is a tumor suppressor gene whose mutations have recently been reported to increase susceptibility for the development of uveal melanoma, cutaneous atypical and epithelioid melanocytic lesions, clear cell renal cell carcinoma, and other tumors. Screening for BAP1 mutation/loss/inactivation and BRAFV600E mutation can be done by immunohistochemistry. We investigated BAP1 and BRAFV600E expression in 193 sporadic melanocytic lesions (11 dermal nevi, 20 congenital nevi, 40 primary and nondesmoplastic melanomas, 40 desmoplastic melanomas, 23 metastatic melanomas, 17 Spitz nevi, 19 atypical Spitz nevi, 8 atypical Spitz tumors, 14 proliferative nodules arising in congenital nevi, 1 nevus during pregnancy) and 30 melanocytic lesions from 3 patients with family history of uveal melanoma and BAP1 germline mutation. Most sporadic melanocytic lesions exhibited positive BAP1 nuclear staining, except for 1 proliferative nodule arising in congenital nevus, 1 desmoplastic, 1 nevoid, and 2 metastatic melanomas. BRAFV600E positivity was demonstrated in 80% of dermal, 5% of congenital, 6% of Spitz, and 5.5% of atypical Spitz nevi; 29% of proliferative nodules arising in congenital nevi; and 24% of primary and nondesmoplastic and 35% of metastatic melanomas. Combined BAP1 loss and BRAFV600E staining was seen in 67% of BAP1 tumor syndrome-associated lesions and in none of the sporadic melanocytic proliferations including Spitz and atypical Spitz nevi and atypical Spitz tumors, with the exception of 1 primary melanoma. The combined BAP1-BRAFV600E+ immunoprofile appears to be a constant feature of BAP1 tumor syndrome-associated melanocytic lesions, and the designation of Spitz nevi or variants thereof appears to be inaccurate for this group of lesions.

Tumours associated with BAP1 mutations

BAP1 (BRCA1-Associated Protein 1) was initially identified as a protein that binds to BRCA1. BAP1 is a tumour suppressor that is believed to mediate its effects through chromatin modulation, transcriptional regulation, and possibly via the ubiquitin-proteasome system and the DNA damage response pathway. Germline mutations of BAP1 confer increased susceptibility for the development of several tumours, including uveal melanoma, epithelioid atypical Spitz tumours, cutaneous melanoma, and mesothelioma. However, the complete tumour spectrum associated with germline BAP1 mutations is not yet known. Somatic BAP1 mutations are seen in cutaneous melanocytic tumours (epithelioid atypical Spitz tumours and melanoma), uveal melanoma, mesothelioma, clear cell renal cell carcinoma, and other tumours. Here, we review the current state of knowledge about the functional roles of BAP1, and summarise data on tumours associated with BAP1 mutations. Awareness of these tumours will help pathologists and clinicians to identify patients with a high likelihood of harbouring germline or somatic BAP1 mutations. We recommend that pathologists consider testing for BAP1 mutations in epithelioid atypical Spitz tumours and uveal melanomas, or when other BAP1-associated tumours occur in individual patients. Tumour tissues may be screened for BAP1 mutations/loss/inactivation by immunohistochemistry (IHC) (demonstrated by loss of nuclear staining in tumour cells). Confirmatory sequencing may be considered in tumours that exhibit BAP1 loss by IHC and in those with equivocal IHC results. If a BAP1 mutation is confirmed in a tumour, the patient's treating physician should be informed of the possibility of a BAP1 germline mutation, so they can consider whether genetic counselling and further testing of the patient and investigation of their family is appropriate. Recognition and evaluation of larger numbers of BAP1-associated tumours will also be necessary to facilitate identification of additional distinct clinico-pathological characteristics or other genotype-phenotype correlations that may have prognostic and management implications.

Lack of GNAQ and GNA11 Germ-Line Mutations in Familial Melanoma Pedigrees with Uveal Melanoma or Blue Nevi

Approximately 10% of melanoma cases are familial, but only 25–40% of familial melanoma cases can be attributed to germ-line mutations in the CDKN2A – the most significant high-risk melanoma susceptibility locus identified to date. The pathogenic mutation(s) in most of the remaining familial melanoma pedigrees have not yet been identified. The most common mutations in nevi and sporadic melanoma are found in BRAF and NRAS, both of which result in constitutive activation of the MAPK pathway. However, these mutations are not found in uveal melanomas or the intradermal melanocytic proliferations known as blue nevi. Rather, multiple studies report a strong association between these lesions and somatic mutations in Guanine nucleotide-binding protein G(q) subunit alpha (GNAQ), Guanine nucleotide-binding protein G(q) subunit alpha-11 (GNA11), and BRCA1-associated protein-1 (BAP1). Recently, germ-line mutations in BAP1, the gene encoding a tumor suppressing deubiquitinating enzyme, have been associated with predisposition to a variety of cancers including uveal melanoma, but no studies have examined the association of germ-line mutations in GNAQ and GNA11 with uveal melanoma and blue nevi. We have now done so by sequencing exon 5 of both of these genes in 13 unique familial melanoma pedigrees, members of which have had either uveal or cutaneous melanoma and/or blue nevi. Germ-line DNA from a total of 22 individuals was used for sequencing; however no deleterious mutations were detected. Nevertheless, such candidate gene studies and the discovery of novel germ-line mutations associated with an increased MM susceptibility can lead to a better understanding of the pathways involved in melanocyte transformation, formulation of risk assessment, and the development of specific drug therapies.